EP1554284B1 - Verfahren zur herstellung der kristallform i von clopidogrel-hydrogensulphat - Google Patents

Verfahren zur herstellung der kristallform i von clopidogrel-hydrogensulphat Download PDF

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Publication number
EP1554284B1
EP1554284B1 EP03750270A EP03750270A EP1554284B1 EP 1554284 B1 EP1554284 B1 EP 1554284B1 EP 03750270 A EP03750270 A EP 03750270A EP 03750270 A EP03750270 A EP 03750270A EP 1554284 B1 EP1554284 B1 EP 1554284B1
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solution
hydrogen sulphate
clopidogrel
formula
hours
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French (fr)
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EP1554284A1 (de
Inventor
Miroslav Veverka
Stefan Vodny
Eva Veverkova
Josef Hajicek
Hana Stepankova
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Zentiva KS
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Zentiva KS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention relates to a new method for manufacturing hydrogen sulphate (alpha S) of the alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester (clopidogrel hydrogen sulphate) in its crystalline Form I.
  • Hydrogen sulphate (alpha S) of the alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester (clopidogrel hydrogen sulphate) of formula I is an anti-thrombotic agent that has been described in patent CZ 274 420 ( EP 281 459 ), dealing with the technology for manufacturing dextrorotatory S enantiomer.
  • the manufacturing method disclosed in the cited patent dwells in reacting the racemic mixture with optically active camphor sulphonic acid and subsequent separating the diastereoisomer.
  • the respective salt of clopidogrel with camphor sulphonic acid is transformed with sodium hydrogen carbonate solution in methylene chloride environment into the optically active base, which is obtained by evaporation of the solvent.
  • the evaporation residue - the optically active base of clopidogrel - is dissolved in acetone, where it is transformed into hydrogen sulphate by adding drops of an equivalent amount of sulphuric acid, under cooling with crushed ice.
  • the melting temperature of the resulting precipitate is stated as 184 °C.
  • Example 6 of the application WO 03/035652 A similar method is described in Example 6 of the application WO 03/035652 . According to this method, reaction of the clopidogrel base and sulphuric acid is carried out in acetone; the product is crystallized and filtered. The filtrate is treated with further sulphuric acid in ethyl acetate, and further portion of the product is crystallized. The melting temperature of the complete product was 186.7 to 187.4 °C.
  • the process for obtaining Form II according to example 1A of this application dwells in introduction of the salt of clopidogrel with camphor sulphonic acid into methylene chloride and its transformation into the base with a solution of potassium carbonate. Methylene chloride is evaporated and the evaporation residue is dissolved in acetone. By adding sulphuric acid, the hydrogen sulphate precipitates out of acetone.
  • the present invention provides a reliable method for obtaining Form I of clopidogrel hydrogen sulphate without detectable impurity of Form II.
  • This invention relates to a method for manufacturing crystalline Form I of clopidogrel hydrogen sulphate, consisting in crystallisation or precipitation of this Form from a solvent selected from the series of C1-C5 alcohols or their esters with C1-C4 acids, optionally of mixtures of alcohols and esters.
  • the manufacturing method described in the prior art thus allows a non-specific preparation of Form I. It has now been found out that if clopidogrel hydrogen sulphate is allowed to crystallise by the procedure according to this invention, Form I having a high and defined content can be obtained in a reproducible way.
  • the substance of this invention is a process for manufacturing crystalline Form I of clopidogrel hydrogen sulphate, which method resides in:
  • crystalline Form I of clopidogrel hydrogen sulphate can be produced in an alternative procedure, residing in:
  • the mixture is stirred until the crystalline phase separates at a temperature between 10 and 15 °C for 1.5 to 2 hours, and then at -5 °C for 8 hours.
  • the product is filtered off on fritted glass S-2 and dried with a stream of air.
  • 1.7 g of clopidogrel hydrogen sulphate Form I with minimal polymorph purity of 98 % and having the melting point of 185 to 187 °C are obtained.
  • 0.5 g of clopidogrel hydrogen sulphate Form II, having the melting point of 177 to 179 °C, are separated out of the mother liquors upon standing at 25 °C.
  • clopidogrel hydrogen sulphate Form I showing the melting point of 184 to 186 °C
  • clopidogrel hydrogen sulphate Form II having the melting point of 177 to 179 °C, is separated upon standing at 25 °C.
  • clopidogrel base 56.9 g clopidogrel base are dissolved in 570 ml of n-butyl acetate and placed in a three-neck round flask, equipped with a thermometer, a KPG stirrer and a dropping funnel. Under mixing, the butyl acetate solution is cooled down to 0 to +5 °C in a water-and-ice bath. The solution is inoculated with crystals of clopidogrel Form I. Under intensive stirring, 9.71 ml of concentrated sulphuric acid (97%) (1.5 equiv.) are added dropwise into the cooled-down solution such that the temperature of the reaction mixture does not exceed +5 °C.
  • clopidogrel base 12.63 g clopidogrel base are dissolved in 126 ml of n-butyl acetate and placed in a three-neck round flask, equipped with a thermometer, a KPG stirrer and a dropping funnel. Under stirring, the butyl acetate solution is cooled down to 0 to +5 °C in a water-and-ice bath. The solution is inoculated with crystals of clopidogrel Form I. Under intensive stirring, 2.4 ml of concentrated sulphuric acid (98%) (1.1 equiv.) are added dropwise into the cooled-down solution such that the temperature of the reaction mixture does not exceed +5 °C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Liquid Crystal Substances (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pyridine Compounds (AREA)

Claims (6)

  1. Verfahren zur Herstellung von Hydrogensulfat (alpha S) des Alpha-(2-chlorphenyl)-6,7-dihydrothieno[3,2]pyridrin-5(4H)-essigsäure-methylester (Clopidogrel Hydrogensulfat) der Formel I
    Figure imgb0003
     in Kristallinform I, dadurch gekennzeichnet, dass die Verbindung der Formel I aus einer Lösung von Clopidogrel in Form der freien Base oder Salz in einem aus einer Reihe von primären, sekundären oder tertiären C1-C5-Alkoholen oder deren Estern mit C1-C4 Carbonsäuren oder optional aus deren Mischungen gewählten Lösungsmittel herausgetrennt wird, unter der Bedingung, dass das Herstellungsverfahren, bestehend daraus, 98% Schwefelsäure zu der Clopidogrelbase in einer Lösung in Aceton bei 20-28°C hinzuzufügen, 5 Stunden umzurühren, bei Temperaturen zwischen 0-10°C abzukühlen, diese Temperatur für 2 Stunden zu halten, das Produkt zu filtern, dann 98% Schwefelsäure in Ethylacetat bei 20-28°C zu dem Filtrat über einen Zeitraum von einer Stunde hinzuzufügen und das Produkt nach 5-stündigem Umrühren zu filtern, mit Aceton zu waschen und 4 Stunden im Vakuumofen zwischen 50 und 55°C zu trocknen, ausgeschlossen wird.
  2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Verbindung der Formel I aus einer Lösung vom Clopidogrel Hydrogensulfat durch Abkühlen herauskristallisiert wird.
  3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Verbindung der Formel I aus einer Lösung von ihrer Base oder ihrem Salz durch Hinzufügen von 0,6 bis 1,1 Äquivalente Schwefelsäure niedergeschlagen wird.
  4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, dass die Verbindung der Formel I aus einer Lösung in einem C1-C5-Alkohol niedergeschlagen wird.
  5. Verfahren nach Anspruch 4, dadurch gekennzeichnet, dass die Ausfällung aus einer Lösung in 2-Propanol durchgeführt wird.
  6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, dass die Ausfällung bei einer Temperatur zwischen -5 und 15°C durchgeführt wird und die Lösung mit Kristallen der Form 1 angeimpft wird.
EP03750270A 2002-08-27 2003-08-26 Verfahren zur herstellung der kristallform i von clopidogrel-hydrogensulphat Revoked EP1554284B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CZ20022906 2002-08-27
CZ20022906A CZ297472B6 (cs) 2002-08-27 2002-08-27 Zpusob výroby clopidogrelu hydrogensulfátu krystalické formy I
PCT/CZ2003/000049 WO2004020443A1 (en) 2002-08-27 2003-08-26 Method for manufacturing crystalline form i of clopidogrel hydrogen sulphate

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EP1554284A1 EP1554284A1 (de) 2005-07-20
EP1554284B1 true EP1554284B1 (de) 2008-10-22

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US (1) US7714133B2 (de)
EP (1) EP1554284B1 (de)
JP (1) JP2006502238A (de)
KR (1) KR20050058492A (de)
AT (1) ATE411998T1 (de)
AU (1) AU2003269673A1 (de)
CA (1) CA2495823A1 (de)
CZ (1) CZ297472B6 (de)
DE (1) DE60324301D1 (de)
EA (1) EA007977B1 (de)
PL (1) PL373578A1 (de)
WO (1) WO2004020443A1 (de)

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WO2005012300A1 (en) * 2003-08-04 2005-02-10 Wockhardt Limited A novel process for the manufacture of (+)-(s)-clopidogrel bisulfate form-i
DE10337773A1 (de) * 2003-08-13 2005-03-24 Krka Tovarna Zdravil, D.D. Kristallisation von festen Formen von Clopidogrel-Additionssalzen
CA2676121A1 (en) * 2003-11-03 2005-07-14 Cadila Healthcare Limited Processes for preparing different forms of (s)-(+)-clopidogrel bisulfate
BRPI0418726A (pt) * 2004-04-09 2007-09-11 Hanmi Pharm Ind Co Ltd naftalenossulfonato de clopidogrel cristalino ou hidrato do mesmo, método para sua preparação e composição farmacêutica contendo o mesmo
SI1740593T1 (sl) 2004-04-19 2016-08-31 Krka, Tovarna Zdravil, D.D., Novo Mesto Postopek za pripravo polimorfne oblike I klopidogrel hidrogen sulfata
EP1756116A1 (de) * 2004-04-20 2007-02-28 Sanofi-Aventis Polymorphie formen von (+)-(s)-alpha-(2-chlorphenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4h)essigsäuremethylester-hydrobromid, clopidrogel-hydrobromid
BRPI0510008A (pt) * 2004-04-20 2007-09-18 Sanofi Aventis sal de clopidogrel e formas polimórficas deste
EP1693375A1 (de) * 2005-02-21 2006-08-23 KRKA, tovarna zdravil, d.d., Novo mesto Verfahren zur Herstellung von Clopidrogel hydrogen sulfat in Form I
US7772398B2 (en) 2005-03-11 2010-08-10 Dr. Reddy's Laboratories, Inc. Process for making crystalline form I of clopidogrel hydrogen sulphate
WO2007017886A1 (en) * 2005-08-11 2007-02-15 Arch Pharmalabs Limited Novel process for preparation of clopidogrel bisulphate polymorphic form i
AU2006292946B2 (en) 2005-09-21 2009-12-10 Chong Kun Dang Pharmaceutical Corp. Novel resinate complex of s-clopidogrel and production method thereof
US20080188663A1 (en) * 2007-01-29 2008-08-07 Ashok Kumar Process for the preparation of crystalline clopidogrel hydrogen sulphate Form I
WO2008093357A2 (en) * 2007-01-29 2008-08-07 Ipca Laboratories Limited Process for preparation of crystalline clopidogrel hydrogen sulphate form i
EP2152078B8 (de) 2007-04-27 2021-03-17 CyDex Pharmaceuticals, Inc. Formulierungen mit clopidogrel und sulfoalkylethercyclodextrin sowie verwendungsverfahren
EP2107061A1 (de) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Herstellungsverfahren für optisch angereichertes Clopidogrel
AU2009264395B2 (en) * 2008-06-24 2013-12-05 Zach System S.P.A. Process for the preparation of clopidogrel hydrogen sulfate crystalline form I
US8236782B2 (en) 2009-05-13 2012-08-07 Cydex Pharmaceuticals, Inc. Pharmaceutical compositions comprising prasugrel and cyclodextrin derivatives and methods of making and using the same
WO2011042804A2 (en) 2009-10-08 2011-04-14 Jubliant Life Sciences Limited An improved process for the preparation of clopidogrel hydrogen sulfate form i
KR101130445B1 (ko) * 2009-10-29 2012-03-27 동아제약주식회사 클로피도그랠 황산수소염 ⅰ형 제조방법
WO2011051976A2 (en) 2009-10-30 2011-05-05 Matrix Laboratories Ltd An improved process for the preparation of clopidogrel bisulfate form i
EP2491044A4 (de) * 2009-11-09 2013-04-24 Pharmazell Gmbh Verbessertes verfahren zur herstellung von clopiodogrel-bisulfat in der kristallform 1
WO2011125069A1 (en) 2010-03-22 2011-10-13 Rpg Life Sciences Limited A process for preparation of crystalline form i of clopidogrel bisulfate
CN102558194A (zh) * 2010-12-11 2012-07-11 山东方明药业股份有限公司 一种硫酸氢氯吡格雷i型的制备方法
CN102875568B (zh) * 2012-09-06 2015-12-09 苏州晶云药物科技有限公司 制备(+)-(s)-氯吡格雷硫酸氢盐纯晶型i的方法
KR101710922B1 (ko) 2015-06-03 2017-02-28 경동제약 주식회사 클로피도그렐 황산염 결정형 i형의 제조방법
CN107118221B (zh) * 2017-05-24 2021-09-07 常州制药厂有限公司 一种硫酸氢氯吡格雷晶型i制备方法
CN107163060B (zh) * 2017-05-24 2021-03-02 常州制药厂有限公司 一种硫酸氢氯吡格雷晶型ii制备方法

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WO2005012300A1 (en) * 2003-08-04 2005-02-10 Wockhardt Limited A novel process for the manufacture of (+)-(s)-clopidogrel bisulfate form-i

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WO2003035652A1 (en) * 2001-10-26 2003-05-01 Merck Generics [Uk] Limited A PROCESS FOR PREPARING ENANTIOMERICALLY PURE α-PHENYL-α-(6,7-DIHYDRO-4H-THIENO[3,2-C]PYRIDIN-5-YL)-ACETIC ACID DERIVATIVES
WO2003051362A2 (en) * 2001-12-18 2003-06-26 Teva Pharmaceutical Industries Ltd. Polymorphs of clopidogrel hydrogensulfate

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CZ297472B6 (cs) 2006-12-13
JP2006502238A (ja) 2006-01-19
EA007977B1 (ru) 2007-02-27
EP1554284A1 (de) 2005-07-20
ATE411998T1 (de) 2008-11-15
US20060041136A1 (en) 2006-02-23
WO2004020443A1 (en) 2004-03-11
PL373578A1 (en) 2005-09-05
AU2003269673A1 (en) 2004-03-19
CA2495823A1 (en) 2004-03-11
CZ20022906A3 (en) 2004-05-12
US7714133B2 (en) 2010-05-11
DE60324301D1 (de) 2008-12-04
KR20050058492A (ko) 2005-06-16
EA200500310A1 (ru) 2005-08-25

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